CA2601129A1 - Crystallisation and purification of glycopyrronium bromide - Google Patents
Crystallisation and purification of glycopyrronium bromide Download PDFInfo
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- CA2601129A1 CA2601129A1 CA002601129A CA2601129A CA2601129A1 CA 2601129 A1 CA2601129 A1 CA 2601129A1 CA 002601129 A CA002601129 A CA 002601129A CA 2601129 A CA2601129 A CA 2601129A CA 2601129 A1 CA2601129 A1 CA 2601129A1
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- 229960002462 glycopyrronium bromide Drugs 0.000 title claims abstract description 19
- 238000002425 crystallisation Methods 0.000 title claims abstract description 16
- 238000000746 purification Methods 0.000 title description 6
- VPNYRYCIDCJBOM-UHFFFAOYSA-M Glycopyrronium bromide Chemical compound [Br-].C1[N+](C)(C)CCC1OC(=O)C(O)(C=1C=CC=CC=1)C1CCCC1 VPNYRYCIDCJBOM-UHFFFAOYSA-M 0.000 title description 2
- 238000000034 method Methods 0.000 claims abstract description 23
- ANGKOCUUWGHLCE-UHFFFAOYSA-N 2-cyclopentyl-2-hydroxy-2-phenylacetic acid (1,1-dimethyl-3-pyrrolidin-1-iumyl) ester Chemical compound C1[N+](C)(C)CCC1OC(=O)C(O)(C=1C=CC=CC=1)C1CCCC1 ANGKOCUUWGHLCE-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000002904 solvent Substances 0.000 claims abstract description 12
- 239000002245 particle Substances 0.000 claims abstract description 9
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 claims abstract description 7
- ANGKOCUUWGHLCE-HKUYNNGSSA-N [(3s)-1,1-dimethylpyrrolidin-1-ium-3-yl] (2r)-2-cyclopentyl-2-hydroxy-2-phenylacetate Chemical compound C1[N+](C)(C)CC[C@@H]1OC(=O)[C@](O)(C=1C=CC=CC=1)C1CCCC1 ANGKOCUUWGHLCE-HKUYNNGSSA-N 0.000 claims abstract description 5
- 238000004519 manufacturing process Methods 0.000 claims abstract description 4
- 229940102396 methyl bromide Drugs 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 17
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 17
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 16
- 239000000203 mixture Substances 0.000 claims description 13
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 9
- 230000008025 crystallization Effects 0.000 claims description 5
- 239000007810 chemical reaction solvent Substances 0.000 claims 2
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 claims 1
- 239000012535 impurity Substances 0.000 description 19
- 238000001953 recrystallisation Methods 0.000 description 12
- 239000008186 active pharmaceutical agent Substances 0.000 description 9
- 229940088679 drug related substance Drugs 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 238000010992 reflux Methods 0.000 description 6
- 239000000463 material Substances 0.000 description 5
- 238000007069 methylation reaction Methods 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 238000005119 centrifugation Methods 0.000 description 3
- 229940126534 drug product Drugs 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- 239000012264 purified product Substances 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000003643 water by type Substances 0.000 description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- FLVFPAIGVBQGET-UHFFFAOYSA-N 1-methylpyrrolidin-3-ol Chemical compound CN1CCC(O)C1 FLVFPAIGVBQGET-UHFFFAOYSA-N 0.000 description 1
- ZMPYMKAWMBVPQE-UHFFFAOYSA-N 2-[(6-chloropyridin-3-yl)methyl-ethylamino]-2-methyliminoacetic acid Chemical compound CCN(CC1=CN=C(C=C1)Cl)C(=NC)C(=O)O ZMPYMKAWMBVPQE-UHFFFAOYSA-N 0.000 description 1
- YODQDGIHQIMBAK-UHFFFAOYSA-N 2-cyclopentyl-2-hydroxy-2-(2-hydroxyphenyl)acetic acid Chemical compound C1CCC(C1)C(C2=CC=CC=C2O)(C(=O)O)O YODQDGIHQIMBAK-UHFFFAOYSA-N 0.000 description 1
- VKIGAWAEXPTIOL-UHFFFAOYSA-N 2-hydroxyhexanenitrile Chemical compound CCCCC(O)C#N VKIGAWAEXPTIOL-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 101150047265 COR2 gene Proteins 0.000 description 1
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical class O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 1
- 101100467189 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) QCR2 gene Proteins 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- -1 ethyl acetate Chemical compound 0.000 description 1
- 239000010419 fine particle Substances 0.000 description 1
- 229940015042 glycopyrrolate Drugs 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 239000003149 muscarinic antagonist Substances 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000010583 slow cooling Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/12—Oxygen or sulfur atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/06—Anti-spasmodics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Urology & Nephrology (AREA)
- Epidemiology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Medicinal Preparation (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Silicates, Zeolites, And Molecular Sieves (AREA)
- Pyrrole Compounds (AREA)
Abstract
A method for the production of crystalline glycopyrronium bromide, comprises the reaction of glycopyrronium base with methyl bromide in a solvent, in which the solvent is selected such that the diastereoisomeric ratio of the product favours the R,S and S,R diastereoisomers over the R,R, and S,S
diastereoisomers, and separating the desired diastereoisomers by one or more controlled crystallisation steps. This method gives a product having a particle size of narrow distribution.
diastereoisomers, and separating the desired diastereoisomers by one or more controlled crystallisation steps. This method gives a product having a particle size of narrow distribution.
Description
CRYSTALLISATION AND PURIFICATION OF GLYCOPYRRONIUM BROMIDE
Field of the Invention This invention relates to a method of crystallisation and purification of the anti-muscarinic drug glycopyrronium bromide.
Backaround of the Invention Glycopyrronium bromide (Glycopyrrolate, US Pharmacopeia) is the higher melting (193.2 C-194.5 C) of two possible diastereoisomeric racemates, i.e.
the erythro racemate. Glycopyrronium bromide is manufactured by the method disclosed in US-A-2956062, utilizing N-methylpyrrolidin-3-ol (NMP) and methyl 1o hydroxycyclopentylmandelate (MCPM), as follows:
OH
NMP OH
0%0 N\ ~ O
OMe O N
Na / Heptane \
75-80% GP Base 1) MeBr / Solvent
Field of the Invention This invention relates to a method of crystallisation and purification of the anti-muscarinic drug glycopyrronium bromide.
Backaround of the Invention Glycopyrronium bromide (Glycopyrrolate, US Pharmacopeia) is the higher melting (193.2 C-194.5 C) of two possible diastereoisomeric racemates, i.e.
the erythro racemate. Glycopyrronium bromide is manufactured by the method disclosed in US-A-2956062, utilizing N-methylpyrrolidin-3-ol (NMP) and methyl 1o hydroxycyclopentylmandelate (MCPM), as follows:
OH
NMP OH
0%0 N\ ~ O
OMe O N
Na / Heptane \
75-80% GP Base 1) MeBr / Solvent
2) MEK / MeOH Recryst.
15-20%
SOC12 . MeOH STAGE 3 90-95%
%OH OH
OH O
O O N Br CPMA
Glycopyrronium Bromide The initial product from the methylation reaction in methyl ethyl ketone (MEK;
stage 3) is isolated as an approximately 50:50 mixture of the two possible pairs of diastereoisomers. In order to obtain the desired drug, i.e. the racemic mixture of the R,S and S,R pair of diastereoisomers, the R,R / S,S pair is removed by recrystallising the crude product from a mixture of methanol and MEK.
In the established manufacturing process, there is no provision to control the particle size of the drug substance. The large and inconsistent particle size produces a physically unstable drug substance following micronisation. Material is difficult to formulate into a drug product suitable for inhalation.
Further, apart from controlling the melting point, the US Pharmacopeia makes no provision for the determination of the amount of the R,R and S,S
diastereoisomeric pair in the active pharmadeutical ingredient.
Commercially available MCPM may contain high levels of impurities. These impurities react competitively in stage 2, to produce high levels of carried through impurities in glycopyrronium base, and then in the final salt.
Summary of the Invention io This invention relates to the production of glycopyrronium bromide utilising a novel crystallization process (Stage 3 in scheme 1). In addition to high purity, a consistent and fine particle size is controlled by the solvent, e.g. a solvent of the formula R'COR2 or R'COOR2 wherein R' and R2 are each alkyl of 1 to 8 C atoms. In addition, the process preferably comprises also a slow cooling rate in the final crystallization steps. The particle size of glycopyrronium bromide produced by this method ensures a physically stable micronised drug substance that is suitable for formulation into a drug product optimized for inhaled delivery.
In a preferred embodiment of the invention, carrying out the methylation reaction in acetone ensures that the ratio of diastereoisomeric pairs is 60:40 in favour of the 2o desired R,S and S,R pair. This ensures a reduction in the number of recrystallisation steps that are required to remove the R,R/ S,S pair.
Description of the Invention Based on information provided herein, one of ordinary skill in the art can readily determine a solvent that is suitable for use in the invention. While acetone is exemplified, other solvents that may be found suitable include esters, e.g. of acetic acid such as ethyl acetate, and other ketones such as methyl isobutyl ketone (MEK).
In the given formulae, R' and R2 are preferably C1-4alkyl, and R' is preferably methyl. A
higher ketone than acetone is preferred for the recrystallisation.
Impurities are efficiently reduced by carrying out the methylation reaction in 3o acetone compared to MEK. Sequential recrystallisations from MEK / methanol systematically eliminate these impurities alongside the R,R / S,S pair of diastereoisomers.
The overall yield of glycopyrronium bromide as a product of the methylation reaction and subsequent purification steps is typically 20-30%. Additional recrystallisation steps can be added should the material from the any given
15-20%
SOC12 . MeOH STAGE 3 90-95%
%OH OH
OH O
O O N Br CPMA
Glycopyrronium Bromide The initial product from the methylation reaction in methyl ethyl ketone (MEK;
stage 3) is isolated as an approximately 50:50 mixture of the two possible pairs of diastereoisomers. In order to obtain the desired drug, i.e. the racemic mixture of the R,S and S,R pair of diastereoisomers, the R,R / S,S pair is removed by recrystallising the crude product from a mixture of methanol and MEK.
In the established manufacturing process, there is no provision to control the particle size of the drug substance. The large and inconsistent particle size produces a physically unstable drug substance following micronisation. Material is difficult to formulate into a drug product suitable for inhalation.
Further, apart from controlling the melting point, the US Pharmacopeia makes no provision for the determination of the amount of the R,R and S,S
diastereoisomeric pair in the active pharmadeutical ingredient.
Commercially available MCPM may contain high levels of impurities. These impurities react competitively in stage 2, to produce high levels of carried through impurities in glycopyrronium base, and then in the final salt.
Summary of the Invention io This invention relates to the production of glycopyrronium bromide utilising a novel crystallization process (Stage 3 in scheme 1). In addition to high purity, a consistent and fine particle size is controlled by the solvent, e.g. a solvent of the formula R'COR2 or R'COOR2 wherein R' and R2 are each alkyl of 1 to 8 C atoms. In addition, the process preferably comprises also a slow cooling rate in the final crystallization steps. The particle size of glycopyrronium bromide produced by this method ensures a physically stable micronised drug substance that is suitable for formulation into a drug product optimized for inhaled delivery.
In a preferred embodiment of the invention, carrying out the methylation reaction in acetone ensures that the ratio of diastereoisomeric pairs is 60:40 in favour of the 2o desired R,S and S,R pair. This ensures a reduction in the number of recrystallisation steps that are required to remove the R,R/ S,S pair.
Description of the Invention Based on information provided herein, one of ordinary skill in the art can readily determine a solvent that is suitable for use in the invention. While acetone is exemplified, other solvents that may be found suitable include esters, e.g. of acetic acid such as ethyl acetate, and other ketones such as methyl isobutyl ketone (MEK).
In the given formulae, R' and R2 are preferably C1-4alkyl, and R' is preferably methyl. A
higher ketone than acetone is preferred for the recrystallisation.
Impurities are efficiently reduced by carrying out the methylation reaction in 3o acetone compared to MEK. Sequential recrystallisations from MEK / methanol systematically eliminate these impurities alongside the R,R / S,S pair of diastereoisomers.
The overall yield of glycopyrronium bromide as a product of the methylation reaction and subsequent purification steps is typically 20-30%. Additional recrystallisation steps can be added should the material from the any given
3 recrystallisation not meet the preferred specification of not more than 0.2%
R,R/S,S.
The following Example (stage 3 of the 3-stage process shown above) illustrates the invention. "Cold" means a temperature of 0-10 C.
Stage 3: Methylation Reaction in Acetone A solution of crude glycopyrronium base (13.0 kg; 42.8 mol) in acetone (130 L) is treated with methyl bromide gas (4.5 kg; 47.4 mol) over 30 minutes while maintaining a temperature between -5 C and 5 C. The mixture is then warmed to between 15 C
and 25 C and maintained at this temperature for 2 hours to ensure complete crystallisation of the glycopyrronium bromide has taken place. The product is filtered by centrifugation, 1o washed with cold acetone (40-60 L) and collected (15. kg).
Stage 3.1: First Recrvstallisation The material (15 kg) is dissolved at reflux in a mixture of methanol (13.0 L) and MEK (90 L). Additional MEK (135 L) is added and reflux (75-85 C) maintained for 30 minutes. The mixture is then cooled to between -1 0 C and 0 C at a rate of 30 C/hour, allowing controlled crystallisation of a purified product which is filtered by centrifugation, washed with cold MEK (30-50 L) and collected (7 kg). The purity of the product from this first recrystallisation is typically not less than 99% and the diastereoisomeric purity is typically 94-95% (by HPLC).
Stage 3.2: Second Recrystallisation The material (7 kg) is dissolved at reflux in a mixture of methanol (10.2 L) and MEK (45 L). Additional MEK(65 L) is added and reflux (75-85 C) maintained for minutes. The mixture is then cooled to between -10 C and 0 C at a rate of 30 C/hour, allowing controlled crystallisation of a purified product which is filtered by centrifugation, washed with cold MEK (20-30 L) and the product collected (5.3 kg). The purity of the product from this recrystallisation is typically not less than 99.9% and the diastereoisomeric purity is typically not less than 99.5% (by HPLC).
Stage 3.3: Third Recrystallisation The material (5.3 kg) is dissolved at reflux in a mixture of methanol (4.2 L) and MEK (33 L). Additional MEK (47 L) is added and reflux (75-85 C) maintained for minutes. The mixture is then cooled to between -10 C and 0 C at a rate of 30 C
/ hour allowing controlled crystallisation of a purified product that is filtered, washed with cold MEK (20 L) and oven dried. The drug substance is a fine white crystalline solid (4.9 kg).
The purity of the product from this first recrystallisation is typically not less than 99.95%
and the diastereoisomeric purity is typically not less than 99.8% (by HPLC).
R,R/S,S.
The following Example (stage 3 of the 3-stage process shown above) illustrates the invention. "Cold" means a temperature of 0-10 C.
Stage 3: Methylation Reaction in Acetone A solution of crude glycopyrronium base (13.0 kg; 42.8 mol) in acetone (130 L) is treated with methyl bromide gas (4.5 kg; 47.4 mol) over 30 minutes while maintaining a temperature between -5 C and 5 C. The mixture is then warmed to between 15 C
and 25 C and maintained at this temperature for 2 hours to ensure complete crystallisation of the glycopyrronium bromide has taken place. The product is filtered by centrifugation, 1o washed with cold acetone (40-60 L) and collected (15. kg).
Stage 3.1: First Recrvstallisation The material (15 kg) is dissolved at reflux in a mixture of methanol (13.0 L) and MEK (90 L). Additional MEK (135 L) is added and reflux (75-85 C) maintained for 30 minutes. The mixture is then cooled to between -1 0 C and 0 C at a rate of 30 C/hour, allowing controlled crystallisation of a purified product which is filtered by centrifugation, washed with cold MEK (30-50 L) and collected (7 kg). The purity of the product from this first recrystallisation is typically not less than 99% and the diastereoisomeric purity is typically 94-95% (by HPLC).
Stage 3.2: Second Recrystallisation The material (7 kg) is dissolved at reflux in a mixture of methanol (10.2 L) and MEK (45 L). Additional MEK(65 L) is added and reflux (75-85 C) maintained for minutes. The mixture is then cooled to between -10 C and 0 C at a rate of 30 C/hour, allowing controlled crystallisation of a purified product which is filtered by centrifugation, washed with cold MEK (20-30 L) and the product collected (5.3 kg). The purity of the product from this recrystallisation is typically not less than 99.9% and the diastereoisomeric purity is typically not less than 99.5% (by HPLC).
Stage 3.3: Third Recrystallisation The material (5.3 kg) is dissolved at reflux in a mixture of methanol (4.2 L) and MEK (33 L). Additional MEK (47 L) is added and reflux (75-85 C) maintained for minutes. The mixture is then cooled to between -10 C and 0 C at a rate of 30 C
/ hour allowing controlled crystallisation of a purified product that is filtered, washed with cold MEK (20 L) and oven dried. The drug substance is a fine white crystalline solid (4.9 kg).
The purity of the product from this first recrystallisation is typically not less than 99.95%
and the diastereoisomeric purity is typically not less than 99.8% (by HPLC).
4 Analytical Methods This method uses a Waters Alliance 2695 HPLC system with a PDA 996 detector, column oven and Waters Empower data system or equivalent:
Column: Astec Cyclobond 12000; 250 mm x 4.6 mm ID
Temperature: 15 C
Injection Volume: 20 pL
Detection: UV at 230 nM
Run Time: 20 min Mobile Phase: 1.0 M triethyl ammonium acetate buffer solution (5.0 ml) mixed with acetonitrile (750 ml) and HPLC water (245 ml) Flow Rate: 1.0 mi /min Gradient: lsocratic Run times and relative response times for R,S/S,Rglycopyrronium bromide (the drug substance) and the R,R/S,S impurity are as follows:
Approx. Run Time RRT
(mins) R,R/S,S 10.3 0.95 F,q,-s-/ 10.8 1 The method has a limit of detection of 0.03% and a limit of quantification of 0.1 %. The process as described is capable of reproducing a drug substance with not more than 0.2% of the R,R/S,S pair.
A HPLC method has -been developed and validated providing an in-process check and test method to control levels of this impurity to < 0.2% in batches of the drug substance. Due to the efficiency of the crystallization required to meet this specification, all other impurities are eliminated. Impurities carried through from impure MCPM can readily be eliminated in the recrystallisation steps.
Stage 1, Purity of MCPM
Batch GC purity Impurity 1 Impurity 2 MCPM 76.8% 15.9% 3.2%
o 0CO2Me Impurity 1 Impurity 2 Stage 2, Glycopyrronium Base Formation from impure MCPM
Yield HPLC Purity No of Imp >0.1 % Impurity 1.1 8.2 kg (54%) 89.7% 4 8.2%
Column: Astec Cyclobond 12000; 250 mm x 4.6 mm ID
Temperature: 15 C
Injection Volume: 20 pL
Detection: UV at 230 nM
Run Time: 20 min Mobile Phase: 1.0 M triethyl ammonium acetate buffer solution (5.0 ml) mixed with acetonitrile (750 ml) and HPLC water (245 ml) Flow Rate: 1.0 mi /min Gradient: lsocratic Run times and relative response times for R,S/S,Rglycopyrronium bromide (the drug substance) and the R,R/S,S impurity are as follows:
Approx. Run Time RRT
(mins) R,R/S,S 10.3 0.95 F,q,-s-/ 10.8 1 The method has a limit of detection of 0.03% and a limit of quantification of 0.1 %. The process as described is capable of reproducing a drug substance with not more than 0.2% of the R,R/S,S pair.
A HPLC method has -been developed and validated providing an in-process check and test method to control levels of this impurity to < 0.2% in batches of the drug substance. Due to the efficiency of the crystallization required to meet this specification, all other impurities are eliminated. Impurities carried through from impure MCPM can readily be eliminated in the recrystallisation steps.
Stage 1, Purity of MCPM
Batch GC purity Impurity 1 Impurity 2 MCPM 76.8% 15.9% 3.2%
o 0CO2Me Impurity 1 Impurity 2 Stage 2, Glycopyrronium Base Formation from impure MCPM
Yield HPLC Purity No of Imp >0.1 % Impurity 1.1 8.2 kg (54%) 89.7% 4 8.2%
5.3 kg (36%) 95.2% 7 2.8%
o o O O
Impurity 1.1 Impurity 2.1 Stage 3, Glycopyrronium Bromide Formation and Purification.
Stage Yield HPLC RS,SR RR,SS Imp 1.2 Imp 2.2 3 18 kg 98.0% 61.6 38.4 1.1 0.5 3.1 7 kg 99.5% 94.2 5.8 0.4 ND
3.2 5.3 kg 99.9% 99.6 0.4 0.1 ND
3.3 4.9 kg (29.6%) 99.96% >99.8 <0.2 ND ND
o o O O
Impurity 1.1 Impurity 2.1 Stage 3, Glycopyrronium Bromide Formation and Purification.
Stage Yield HPLC RS,SR RR,SS Imp 1.2 Imp 2.2 3 18 kg 98.0% 61.6 38.4 1.1 0.5 3.1 7 kg 99.5% 94.2 5.8 0.4 ND
3.2 5.3 kg 99.9% 99.6 0.4 0.1 ND
3.3 4.9 kg (29.6%) 99.96% >99.8 <0.2 ND ND
6 o D"'.
\Br N + Br-N
Impurity 1.2 Impurity 2.2 ND = Not Detected This Example validates the purification procedure, demonstrating that even poor quality MCPM can be processed to drug substance of excellent quality. The elimination of these impurities is apparently the consequence of controlled recrystallisation.
Uncontrolled crystallization leads to an impure product with an inconsistent particle size distribution. It was surprising to find the controlled cooling rate employed not only defined a high level of purity but also provided control of particle size distribution and 1o uniform morphological habit, as shown by imaging. Subsequent micronisation of this product has provided a physically stable drug substance that is suitable for formulation into a drug product optimized for inhaled delivery.
\Br N + Br-N
Impurity 1.2 Impurity 2.2 ND = Not Detected This Example validates the purification procedure, demonstrating that even poor quality MCPM can be processed to drug substance of excellent quality. The elimination of these impurities is apparently the consequence of controlled recrystallisation.
Uncontrolled crystallization leads to an impure product with an inconsistent particle size distribution. It was surprising to find the controlled cooling rate employed not only defined a high level of purity but also provided control of particle size distribution and 1o uniform morphological habit, as shown by imaging. Subsequent micronisation of this product has provided a physically stable drug substance that is suitable for formulation into a drug product optimized for inhaled delivery.
Claims (10)
1. A method for the production of crystalline glycopyrronium bromide, which comprises the reaction of glycopyrronium base with methyl bromide in a solvent, in which the solvent is selected such that the diastereoisomeric ratio of the product favours the R,S and S,R diastereoisomers over the R,R, and S,S diastereoisomers, and separating the desired diastereoisomers by one or more controlled crystallisation steps.
2. A method according to claim 1, wherein the reaction solvent and also the solvent in which the crystallization is conducted each comprise the same or different compounds of the formula R1COR2 or R1COOR2 wherein R1 and R2 are independently C1-8 alkyl.
3. A method according to claim 2, wherein the reaction solvent is acetone.
4. A method according to claim 2 or claim 3, wherein the crystallisation solvent comprises methyl ethyl ketone or methyl isobutyl ketone.
5. A method according to claim 4, wherein the crystallisation solvent is a mixture of methyl ethyl ketone and methanol.
6. A method according to any preceding claim, wherein the diastereoisomeric purity of the product is more than 99.8% R,S/S,R.
7. A method according to any preceding claim, wherein the particle size of the product is less than 100 µm.
8. A method according to claim 7, wherein the particle size is less than 50 µm.
9. A method according to any preceding claim, wherein the diastereoisomeric ratio is at least 60:40 in favour of the R,S / S,R- pair.
10. Crystalline glycopyrronium bromide obtainable by a method according to any preceding claim, having a particle size of narrow distribution.
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| Application Number | Priority Date | Filing Date | Title |
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| GBGB0504463.1A GB0504463D0 (en) | 2005-03-03 | 2005-03-03 | Method of crystallisation and purification |
| GB0504463.1 | 2005-03-03 | ||
| PCT/GB2006/000770 WO2006092617A1 (en) | 2005-03-03 | 2006-03-03 | Crystallisation and purification of glycopyrronium bromide |
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| US20090005577A1 (en) * | 2007-06-29 | 2009-01-01 | Nikolai Kraiouchkine | Method of producing 1-substituted 3-pyrrolates |
| KR101290893B1 (en) * | 2009-04-09 | 2013-07-29 | 노파르티스 아게 | Process for preparing pyrrolidinium salts |
| CA2802584C (en) * | 2010-06-14 | 2018-08-21 | Chiesi Farmaceutici S.P.A. | Crystal form of glycopyrronium chloride |
| CN103159659A (en) * | 2011-12-19 | 2013-06-19 | 沈阳药科大学 | Preparation method of muscarinic receptor antagonist glycopyrronium bromide |
| CN102627595A (en) * | 2012-03-09 | 2012-08-08 | 徐奎 | Method for preparation of glycopyrronium bromide |
| US9006462B2 (en) | 2013-02-28 | 2015-04-14 | Dermira, Inc. | Glycopyrrolate salts |
| EP3842419B1 (en) | 2013-02-28 | 2024-04-03 | Journey Medical Corporation | Method of making threo glycopyrrolate tosylate |
| US8558008B2 (en) | 2013-02-28 | 2013-10-15 | Dermira, Inc. | Crystalline glycopyrrolate tosylate |
| CN103553996B (en) * | 2013-11-13 | 2016-01-20 | 北京三泉医药技术有限公司 | Anticholinergic pharmaceutical composition |
| US9926270B2 (en) | 2014-08-20 | 2018-03-27 | Dermira, Inc. | Process for production of glycopyrronium tosylate |
| CZ2014680A3 (en) | 2014-10-06 | 2016-04-13 | Zentiva, K.S. | Process for preparing glycopyrronium bromide |
| US9925168B2 (en) * | 2016-01-22 | 2018-03-27 | Chiesi Farmaceutici S.P.A. | Preparation of micronized particles of an antimuscarinic compound by hydrodynamic cavitation |
| CN107345945B (en) * | 2016-05-05 | 2019-12-17 | 辽宁药联制药有限公司 | High performance liquid chromatography method for resolving glycopyrronium bromide enantiomer and checking impurities |
| PT109445B (en) * | 2016-06-08 | 2018-11-06 | Hovione Farm Sa | CRYSTALINE PHARMACEUTICAL CO-CRYSTALS OF LACTOSE GLYCOPYRONIUM BROMETTE |
| CN107915666A (en) * | 2016-10-09 | 2018-04-17 | 四川海思科制药有限公司 | A kind of glycopyrronium bromide compound |
| WO2022079194A1 (en) | 2020-10-14 | 2022-04-21 | Pcas | Process for the production of glycopyrronium tosylate |
| CN113234003B (en) * | 2021-04-23 | 2024-02-02 | 广东嘉博制药有限公司 | Glycopyrronium bromide and preparation method thereof |
| CN114428131B (en) * | 2021-12-27 | 2023-09-15 | 山东泰合医药科技有限公司 | Detection method for resolving diastereoisomers of glycopyrronium bromide intermediate |
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| EP1369414A1 (en) | 1996-11-11 | 2003-12-10 | Christian R. Noe | Enantiomerically pure Arylcycloalkyl hydroxycarboxylic esters, processes for their preparation and their use as modulators of muscarinic receptors |
| AT412088B (en) * | 2002-12-18 | 2004-09-27 | Pharmacon Forschung & Beratung Gmbh | METHOD FOR PRODUCING THE R, R OR S, S CONFIGURED GLYCOPYRRONIUM ISOMERS |
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| JP5319119B2 (en) | 2013-10-16 |
| JP2008531674A (en) | 2008-08-14 |
| IL185576A0 (en) | 2008-01-06 |
| NO20074558L (en) | 2007-09-28 |
| ZA200707512B (en) | 2008-11-26 |
| MX2007010729A (en) | 2007-11-08 |
| AU2006219727A1 (en) | 2006-09-08 |
| BRPI0609057A2 (en) | 2010-02-17 |
| ATE431337T1 (en) | 2009-05-15 |
| CN101133021A (en) | 2008-02-27 |
| DK1856041T3 (en) | 2009-08-24 |
| IL185576A (en) | 2011-11-30 |
| KR20070113263A (en) | 2007-11-28 |
| EP1856041A1 (en) | 2007-11-21 |
| AU2006219727B2 (en) | 2010-03-04 |
| DE602006006808D1 (en) | 2009-06-25 |
| CN101133021B (en) | 2011-01-19 |
| US8846954B2 (en) | 2014-09-30 |
| US20080227988A1 (en) | 2008-09-18 |
| NZ561293A (en) | 2010-05-28 |
| KR101267108B1 (en) | 2013-05-23 |
| WO2006092617A1 (en) | 2006-09-08 |
| PT1856041E (en) | 2009-07-21 |
| EP1856041B1 (en) | 2009-05-13 |
| GB0504463D0 (en) | 2005-04-13 |
| CA2601129C (en) | 2013-04-30 |
| ES2326132T3 (en) | 2009-10-01 |
| NO340220B1 (en) | 2017-03-20 |
| HK1104817A1 (en) | 2008-01-25 |
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